Solutions of barbituric compounds



Patented July 29, 1952 UNITED STATE S 'PAT'E OFFICE '2,605,,2l)9 .SDLUIIQNS :BARBITUlRIC COMPOUNDS "Malcolm 1D. Bray, Noblesyilleylnd .assignor ito Eli Lilly and .Gompany, Indianapolis, Ind., .a corporationnfiIndiana iNo'Drawing. Application November 3, 1950, Serial No. 194,034

fi'fllaims. 1 This is a continuation-impart of U. S. patent application Serial 'No. 124,248 filed October "28, 1949, now abandoned.

"My invention relates to stable aqueous solutions of barbituric acids and their salts.

'Barbituric acids and their salts are important as anesthetic and hypnotic agents. In addition to oral administration of the barbitur'ic compounds in the form of capsules or tablets, an important use is their parenteral administration by injection f or surgical anesthesia, for which aqueous solutions of the barbituric acid salts have been-employed. 7

It is known that barbiturate salts are unstable in aqueous solution and that the salts decompose upon standing in "such solutions and throw down a precipitate. Hence, the barbiturate salts cannot be "supplied to the trade in the for-m of aqueous solutions ready for parenteral administration since the period elapsing "between their manufacture and their use is sufficiently lengthy to permit an appreciable decomposition of the barbiturate and the deposition of a relatively large amount of precipitate. The barbituric acids themselves have been unsuitable for the preparation of aqueous solutions, since not only do the barbituric acids suffer the degradative changes undergone 'by the salts, but in addition are 'too slightly soluble in water to permit the preparation of water solutions having a therapeutically useful concentration of dissolved .bar- -bituric acid. Consequently, it has -been the re quired practice to supply barbiturates :for parenteral administration in the dorm of a dual package consising of an ampoule ofv a dry 'barb'ituric .acid salt, and an ampoule of water to be used for dissolving the barbiturate immediately prior v.to itstherapeutic administration. The obvious disadvantages .of such procedure have for many acids and .salts of barbituric acids, are obtained by providing compositions comprising essentially the barbituric acids or their salts dissolved in a mixture .of water and ya polyalky-lene glycol. The solutions are quite stable, and accelerated aging tests have indicated that they possess a stability of many years duration. Moresurprisingly, I have tound the solutions are sufuciently stable to permit their sterilization by heating .in :boiling water, or even iautoclaving :at a temperature [of about 125 C. The advantages oi-such solutions are apparent since a stability of this nature ':not only permits the anesthetic to be marketed in .a form suitable .for immediate use, but also permits the ready sterilization of the finished ampoules and thus :avoids the disadvantages attending the manufacture and filling of ampoules under absolutely sterile techniques.

In providing my novel solutions of barbituric compounds, I simply dissolve the barbituric compound in a mixture of water and the polyalkylene glycol. Alternatively, solutions of the barbituricacidsalts can be obtained by dissolving the salt in water and adding thereto the polyalkylene glycol, and solutions of the barbituric acids are obtained by dissolving the acid .in the polyalkylene glycol and adding the required amount 'of water. Solutions so prepared are filled and sealed into ampoules, and sterilized by standard methods, such as by successive heatings in boiling water or by heating in an autoclave.

Specific examples of solutions employing my invention are given below. In the examples the amounts of the .ingredients employed are expressed in parts by weight.

Example .1

An aqueous composition containing about 5 percent on a weight-volume basis of calcium isoamyl-ethyl-barbiturate.is obtained by mixing .the ingredients listed below in the quantities iven:

When the parts by weight .givenabove are chosen in grams, the aqueous solution has a total volume of ml. and each ml. of solution contains about 50 mg. of sodium isoamyl-ethylbarbiturate.

.An aqueous composition containing about 5 percent on a weight-volume basis of isoamylethyl-barbituric acid is obtained by dissolving the barbituric acid in a mixture of Water and poly- ;thylene glycol 600 in the proportions given elow:

- Parts lsoamyl-ethylebarbituric acid 5 Water 33 v Polyethylene glycol 600 '75 Example-3 An aqueous composition containing 5 percent 3 on a weight-volume basis of ammonium propylmethylcarbinyl-allyl-barbiturate is as follows:

In place of the ammonium propylmethylcarbinyl-allyl-barbiturate used in Example 3, the bar-- bituric acid can be employed in the same proportion to give a stable solution of propylmethyl carbinyl-allyl-barbituric acid.

Example 5 r An aqueous composition containing about12;5

percent on a weight-volume basis of sodium ethyl-( l-methylbutyl) -thiobarbiturate is as follows:

' w Par-ts Sodium 'ethyl-(l-methylbutyl) -thio=barbiturate 2.5 Water 45 Carbowax 1500 Example 6 An aqueous composition containing about 5 percent on a weight-volume basis of potassium ethyl-(l-methylbutyl)barbiturate is as follows:

I n I I v v t 7 Parts Potassium ethyl-(l-methylbutyl) barbiturate e 5 Water 45 7 Parts Sodium 5-ethyl-5-(methyl-l-butenyl)-barbiturate 3 Water 45 Polyethylene glycol 600 .I 59.8

Example 8 An aqueous composition containing about 5 percent on aweight-volume basis of sodium 5-n-amyl-5-ethylbarbiturate is as follows:

V V V v Parts 5-n-amyl-5-ethylbarbituric acid l 5 Polyethylene glycol'200 50 50 percent aqueous sodium hydroxide solution 1.5

Water q. s. .100

An aqueous composition containing sodium propylmethyl carbinyl allylbarbiturate is prepared in the same proportions as those given in Example 8, starting with 5epropylmethylcarbinyl 5-allylbarbituric acid.

I Example 10 An aqueous composition of sodium spiro(2- ethyl 3,5 dimethylcyclopentane) 2 thio barbiturate is as follows: I

Parts I Sodium spiro(2 ethyl 3,5 dimethylcyclopentane)-2-thiobarbiturate 2.5 Water 10 Polyethylene glycol 200 Water 'q. -s 100 The above aqueous compositions are characterized. by an exceptional stability and an ability to withstand without decomposition, sterilization by methods employing heat.

For illustrative purposes, the polyalkylene glycols employed in the above examples are polyethylene glycols available to the trade under the generic name polyethylene glycol, or Carbowax, the latter term being employed for the polyethylene glycols of higher molecular weight. The numeral appearing in the designation of the polyethylene glycol refers to the average molecular weight of the glycol.

The amount of polyalkylene glycol required for stability of the aqueous barbiturate salt solution varies to a degree depending upon the innate stability of the barbiturate. Generally speaking, aqueous solutions of barbituric compounds (i. e., salts and acids) containing about 30 to about percent by volume of polyalkylene glycol are stable over longperiods of time and possess-a sumcient degree of stability that permits their sterilization by heat. However, with certain of the barbituric compounds of pronounced instability, such as for example isoamyl-ethyl-barbituric' acid and its salts, it is preferable to employ a relatively larger. proportion of polyalkylene glycol in the V aqueous solutiom and with these less stable barbituric compounds solutions containing up to about '75 percent of polyalkylene glycol should be employed to obtain a high degree of stability.

The polyalkylene glycols useful for the purpose of my invention may vary widely in their degree of polymerization as measured-- or expressed by the average molecular weight of the polyalkylene glycol. Thus, polyalkylene glycols whose degree of polymerization is such that-their average molecular weights range from 200 to about 4,000 are quite satisfactory for the purpose of my invention. Referring again to the commercially available polyethylene glycols of the Carbowax. series for illustrative purposes, members of this series from polyethylene glycol 200 to Carbowax 4000 are satisfactory in pro- .viding stable barbiturate solutions. Polyalkylene glycols of average molecular weight greater than tions, but are less desirable for the purpose of this invention since the solutions possessa relatively great viscosity and are therefore less easily administered parenterally. L

The barbituric acids and salts employed in my invention are those having therapeutic usefulnes's as hypnotic agents Many of such compounds are known to the art. The sodium salts of the barbituric acids are the compounds which have hitherto been most extensively employed 'in the therapeutic field, but other salts such as. the potassium, calcium, magnesium and ammonium salts are also efiicacious therapeutic agents and can be employed in my invention. Furthermore, as pointed out hereinabove, by means of my invention the barbituric acidsthemselves can be employed for parenteral administration, The use of solutions of the barbituric acids avoids the disadvantageously high pI-I exhibited by water solutions of the barbituric acid salts.

I claim: 1. An injectable therapeutic composition comprising essentially a therapeutically usefulbarbituric compound of the class consisting of a barbituric acid and its salt, dissolved in an aqueous composition consisting of water and from about 30 to about percent of a p olyalkylene glycol having an average molecular weight within the range of about 200 to about 4000'.

2. An injectable therapeutic composition comprising essentially a therapeutically useful barbituric acid dissolved in an aqueous composition consisting of water and from about 30 to about '15 percent of a polyalkylene glycol having an average molecular weight within the range of about 200 to about 4000.

3. An injectable therapeutic composition comprising essentially a therapeutically useful salt of a barbituric acid dissolved in an aqueous composition consisting of water and from about 30 to about '75 percent of a polyalkylene glycol having an average molecular weight within the range of about 200 to about 4000.

4. An injectable therapeutic composition com prising essentially sodium isoamyl-ethyl-barbiturate dissolved in an aqueous composition of water and from about 30 to about '75 percent polyethylene glycol having an average molecular weight within the range of about 200 to about 5. An injectable therapeutic composition comprising essentially sodium ethyl-(l-methylbutyl) thiobarbiturate dissolved in an aqueous composition of water and from about 30 to about 75 percent of polyethylene glycol having an aver- I 6. An injectable therapeutic composition comprising essentially sodium propylmethylcarbinylallyl barbiturate dissolved in an aqueous com-. position of water and from about to about percent of polyethylene glycol having an average molecular weight within the range of about 200 to about 4,000.

- MALCOLM D. BRAY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Bockmuhl Feb. 28, 1939 OTHER REFERENCES Number 

1. AN INJECTABLE THERAPEUTIC COMPOSITION COMPRISING ESSENTIALLY A THERAPEUTICALLY USEFUL BARBITURIC COMPOUND OF THE CLASS CONSISTING OF A BARBITURIC ACID AND ITS SALT, DISSOLVED IN AN AQUEOUS COMPOSITION CONSISTING OF WATER AND FROM ABOUT 30 TO ABOUT 75 PERCENT OF A POLYALKYLENE GLYCOL HAVING AN AVERAGE MOLECULAR WEIGHTWITHIN THE RANGE OF ABOUT 200 TO ABOUT
 4000. 